IDH1突变体通过重塑糖脂代谢促进肿瘤发生的机理

In recent years various mutants of IDH1 Arg132 have been found to produce high level of 2-hydroxyglutarate (2-HG) which in turn promotes the generation of a variety of maliganant tumors such as gliomas and acute myeloid leukemia (AML). Our previous studies showed that 2-HG could promote tumorigenesis through inhibition of cell death pathways mediated by JNK, RIP3 and p53. It has been well understood that metabolic remodeling of glucose and lipid plays important role in tumorigenesis. So it may be very helpful for the reveal of mechanism underlying tumorigenesis promoted by IDH1 mutants to investigate the global metabolic remodeling of glucose and lipid caused by these mutants, especially considering the insufficiency of such a reseach. As liver is the core organ for metabolism of glucose and lipid of mouse, we created conditional knock-in mouse of IDH1 R132Q in mouse liver and did some preliminary work to characterize its metabolic features. We observed high incidence rate of hepatoma and significant remodeling of glucose and lipid metabolism in Knock-in mice compared with wildtype mice. Knock-in mice were decreased for blood glucose level, glycogen synthesis and fatty acid synthessis, and increase for glucose consumption and fatty acid β-oxidation in comparison with wildtype mice. In this project, we will further try to clarify the molecular mechanism underlying such a metabolic remodeling and reveal its relationship with tumorigenesis driven by IDH1 mutants. Moreover we will verify what we found in mouse model by repeating corresponding experiments in tumor cell lines and clinical tumor samples harboring IDH1 mutations. We will also try to identify the potential metabolic targets for the treatment of tumors carrying IDH1 mutations.

IDH1 Arg132位点的各种突变体能产生大量的癌性代谢产物2-HG，导致胶质瘤、白血病等多种肿瘤的发生。我们之前的研究表明2-HG能通过抑制JNK、RIP3和p53死亡信号通路促进肿瘤发生。糖脂代谢重塑在肿瘤发生中起重要作用，在动物水平全面研究IDH1的突变体重塑糖脂代谢的机理对进一步揭示其致癌机理有重要意义。目前在动物水平对IDH1突变体重塑糖脂代谢的研究很少。肝脏是糖脂代谢的核心器官，在前期工作中我们构建了IDH1 R132Q在肝脏特异性基因敲入的小鼠，发现该小鼠肝脏会自发形成肿瘤，且糖脂代谢重塑显著：血糖低、糖原合成减少、葡萄糖的消耗速率明显增强，脂肪酸合成减少而脂肪酸的β-氧化则明显增强。本项目将进一步揭示导致这种代谢重塑的分子机理及其在肿瘤发生中的作用，并在IDH1突变的肿瘤细胞系和临床肿瘤标本中加以验证。同时，寻找针对IDH1突变体引起的肿瘤的治疗靶点。

IDH1 Arg132位点的各种突变体能产生大量的癌性代谢产物2-HG，导致胶质瘤、白血病等多种肿瘤的发生。我们之前的研究表明2-HG能通过抑制JNK、RIP3和p53信号通路促进肿瘤发生。糖脂代谢重塑在肿瘤发生中起重要作用，在动物水平全面研究IDH1突变体重塑糖脂代谢的机理对进一步揭示其致癌机理有重要意义。目前在动物水平对IDH1突变体重塑糖脂代谢的研究很少。肝脏是糖脂代谢的核心器官，在前期工作中我们构建了IDH1 R132Q在肝脏特异性基因敲入的小鼠。在本项目的研究中，我们发现该小鼠肝脏会自发形成肿瘤，且糖脂代谢重塑显著：血糖低、糖原合成减少、葡萄糖的消耗速率明显增强，脂肪酸合成减少而脂肪酸的β-氧化则明显增强。在机理方面，IDH1突变体可以通过上调c-Myc和HIF-1α这两个转录因子，进而上调HK1、GCK和LDHA等糖酵解相关的代谢酶，最终促进细胞糖酵解的能力。2-HG与α-KG在结构式极其类似，我们发现2-HG可以与α-KG脱氢酶结合并抑制其酶活性，进而抑制TCA循环。在脂代谢方面，IDH1突变的细胞脂肪酸的β-氧化过程中的代谢酶CPT1A、TPβ、ACADL、ACOX1和CD36等表达水平均显著上升，这促进了脂肪酸的β-氧化。IDH1突变细胞对糖酵解和脂肪酸氧化依赖性的增加，使其对糖酵解和脂肪酸氧化的抑制更加敏感。在低葡萄糖的情况下，抑制CPT1A能特异性引起突变体细胞ATP下降、ROS上升、细胞死亡、成瘤能力降低，说明CPT1A是一个重要靶点；且联合靶向CPT1A和GLS1对肿瘤的抑制效果更佳。. 综上，本研究发现IDH1突变引起糖脂代谢发生显著的变化，CPT1A为含IDH1突变体肿瘤的一个潜在治疗靶点，联合抑制CPT1A和GLS1有望成为IDH1突变体肿瘤潜在的治疗策略。